Novel compounds

ABSTRACT

The present invention relates to Compounds of formula (I) and salts thereof: 
     
       
         
         
             
             
         
       
     
     wherein R 1  is n-C 3-6 alkyl; R 2  is hydrogen or methyl; R 3  is hydrogen or C 1-6 alkyl, and m is an integer having a value of 0 to 3; are inducers of human interferon. Compounds which induce human interferon may be useful in the treatment of various disorders, for example the treatment of allergic diseases and other inflammatory conditions, for example allergic rhinitis and asthma, infectious diseases and cancer, and may also be useful as vaccine adjuvants.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to compounds, processes for theirpreparation, compositions containing them, to their use in the treatmentof various disorders in particular allergic diseases and otherinflammatory conditions for example allergic rhinitis and asthma,infectious diseases, and cancer, and as vaccine adjuvants.

BACKGROUND OF THE INVENTION

Vertebrates are constantly threatened by the invasion of microorganismsand have evolved mechanisms of immune defence to eliminate infectivepathogens. In mammals, this immune system comprises two branches; innateimmunity and acquired immunity. The first line of host defence is theinnate immune system, which is mediated by macrophages and dendriticcells. Acquired immunity involves the elimination of pathogens at thelate stages of infection and also enables the generation ofimmunological memory. Acquired immunity is highly specific, due to thevast repertoire of lymphocytes with antigen-specific receptors that haveundergone gene rearrangement.

Central to the generation of an effective innate immune response inmammals are mechanisms which bring about the induction of interferonsand other cytokines which act upon cells to induce a number of effects.In man, the type I interferons are a family of related proteins encodedby genes on chromosome 9 and encoding at least 13 isoforms of interferonalpha (IFNα) and one isoform of interferon beta (IFNβ). Interferon wasfirst described as a substance which could protect cells from viralinfection (Isaacs & Lindemann, J. Virus Interference. Proc. R. Soc. Lon.Ser. B. Biol. Sci. 1957: 147, 258-267). Recombinant IFNα was the firstapproved biological therapeutic and has become an important therapy inviral infections and in cancer. As well as direct antiviral activity oncells, interferons are known to be potent modulators of the immuneresponse, acting on cells of the immune system (Gonzalez-Navajas J. M.et al Nature Reviews Immunology, 2012; 2, 125-35).

Toll-like receptors (TLRs) are a family of ten Pattern RecognitionReceptors described in man (Gay, N. J. et al, Annu. Rev. Biochem., 2007:46, 141-165). TLRs are expressed predominantly by innate immune cellswhere their rôle is to monitor the environment for signs of infectionand, on activation, mobilise defence mechanisms aimed at the eliminationof invading pathogens. The early innate immune-responses triggered byTLRs limit the spread of infection, while the pro-inflammatory cytokinesand chemokines that they induce lead to recruitment and activation ofantigen presenting cells, B cells, and T cells. The TLRs can modulatethe nature of the adaptive immune-responses to give appropriateprotection via dendritic cell-activation and cytokine release (Akira S.et al, Nat. Immunol., 2001: 2, 675-680). The profile of the responseseen from different TLR agonists depends on the cell type activated.

TLR7 is a member of the subgroup of TLRs (TLRs 3, 7, 8, and 9),localised in the endosomal compartment of cells which have becomespecialised to detect non-self nucleic acids. TLR7 plays a key rôle inanti-viral defence via the recognition of ssRNA (Diebold S. S. et al,Science, 2004: 303, 1529-1531; and Lund J. M. et al, PNAS, 2004: 101,5598-5603). TLR7 has a restricted expression-profile in man and isexpressed predominantly by B cells and plasmacytoid dendritic cells(pDC), and to a lesser extent by monocytes. Plasmacytoid DCs are aunique population of lymphoid-derived dendritic cells (0.2-0.8% ofPeripheral Blood Mononuclear Cells (PBMCs)) which are the primary type Iinterferon-producing cells secreting high levels of interferon-alpha(IFNα) and interferon-beta (IFNβ) in response to viral infections (LiuY-J, Annu. Rev. Immunol., 2005: 23, 275-306).

Administration of a small molecule compound which could stimulate theinnate immune response, including the activation of type I interferonsand other cytokines via Toll-like receptors, could become an importantstrategy for the treatment or prevention of human diseases. Smallmolecule agonists of TLR7 have been described which can induceinterferon alpha in animals and in man (Takeda K et al, Annu. Rev.Immunol., 2003: 21, 335-76). TLR7 agonists include imidazoquinolinecompounds such as imiquimod and resiquimod, oxoadenine analogues andalso nucleoside analogues such as loxoribine and 7-thia-8-oxoguanosinewhich have long been known to induce interferon alpha (Czarniecki. M.,J. Med, Chem., 2008: 51, 6621-6626; Hedayat M. et al, Medicinal ResearchReviews, 2012: 32, 294-325). This type of immunomodulatory strategy hasthe potential to identify compounds which may be useful in the treatmentof allergic diseases (Moisan J. et al, Am. J. Physiol. Lung Cell Mol.Physiol., 2006: 290, L987-995), viral infections (Horcroft N. J. et al,J. Antimicrob. Chemther, 2012: 67, 789-801), cancer (Krieg A., Curr.Oncol. Rep., 2004: 6(2), 88-95), other inflammatory conditions such asirritable bowel disease (Rakoff-Nahoum S., Cell., 2004, 23, 118(2):229-41), and as vaccine adjuvants (Persing et al. Trends Microbiol.2002: 10(10 Suppl), 532-7).

More specifically, allergic diseases are associated with a Th2-biasedimmune-response to allergens. Th2 responses are associated with raisedlevels of IgE, which, via its effects on mast cells, promotes ahypersensitivity to allergens, resulting in the symptoms seen, forexample, in asthma and allergic rhinitis. In healthy individuals theimmune-response to allergens is more balanced with a mixed Th2/Th1 andregulatory T cell response. TLR7 ligands have been shown to reduce Th2cytokine and enhance Th1 cytokine release in vitro and to ameliorateTh2-type inflammatory responses in allergic lung models in vivo (DuechsM. J., Pulmonary Pharmacology & Therapeutics, 2011: 24, 203-214; Fili L.et al, J. All. Clin. Immunol., 2006: 118, 511-517; Tao et al, Chin. Med.J., 2006: 119, 640-648; Van L. P. Eur. J. Immunol., 2011: 41,1992-1999). Thus TLR7 ligands have the potential to rebalance theimmune-response seen in allergic individuals and lead to diseasemodification. Recent clinical studies with the TLR7 agonist have shownrepeated intranasal stimulation of TLR7 to produce a sustained reductionin the responsiveness to allergen in patients with both allergicrhinitis and allergic asthma (Greiff L. Respiratory Research, 2012: 13,53; Leaker B. R. et al, Am. J. Respir. Crit. Care Med., 2012: 185,A4184).

In the search for novel small molecule inducers of human interferon IFNαan assay strategy has been developed to characterise small molecule(regardless of mechanism) which is based on stimulation of primary humandonor cells or whole blood with compounds, and is disclosed herein.

SUMMARY OF THE INVENTION

In a first aspect, the present invention is directed to compounds offormula (I) and salts thereof:

wherein:R₁ is n-C₃₋₆alkyl;R₂ is hydrogen or methyl;R₃ is hydrogen or C₁₋₆alkyl;m is an integer having a value of 0 to 3.

Certain compounds of the invention have been shown to be inducers ofhuman interferon and may possess a desirable developability profilecompared to known inducers of human interferon. In addition, certaincompounds of the invention may also show selectivity for IFNα withrespect to TNFα. Compounds which induce human interferon may be usefulin the treatment of various disorders, for example the treatment ofallergic diseases and other inflammatory conditions, for exampleallergic rhinitis and asthma, the treatment of infectious diseases andcancer. Accordingly, the invention is further directed to pharmaceuticalcompositions comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof. The present invention is further directed tomethods of treatments of disorders associated therewith using a compoundof formula (I) or a pharmaceutically acceptable salt thereof, or apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt thereof.

The compounds of the invention may also have use as vaccine adjuvants.Consequently, the present invention is further directed to a vaccinecomposition comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, and an antigen or antigen composition.

Certain compounds of the invention are potent immunomodulators andaccordingly, care should be exercised in their handling.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention is directed to compounds offormula (I) and salts thereof:

wherein:R₁ is n-C₃₋₆alkyl;R₂ is hydrogen or methyl;R₃ is hydrogen or C₁₋₆alkyl;m is an integer having a value of 0 to 3.

In a further aspect, R₁ is n-butyl.

In a further aspect, R₂ is hydrogen.

In a further aspect, m is an integer having a value of 0 or 1.

In a further aspect, R₃ is isopropyl.

Examples of compounds of formula (I) are provided in the followinggroup, and form a further aspect of the invention:

-   2-butyl-7-(3-(piperidin-4-yl)propyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;-   2-butyl-7-(3-(1-isopropylpiperidin-4-yl)propyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;    and-   2-butyl-7-(2-(piperidin-4-yl)ethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;    and salts thereof.

As used herein, the term “alkyl” refers to a saturated, hydrocarbonchain having the specified number of member atoms. Unless otherwisestated, the term ‘alkyl’ includes straight and branched alkyl groups.For example, C₁₋₆alkyl refers to a saturated, straight or branchedhydrocarbon chain having from 1 to 6 carbon atoms, such as ethyl andisopropyl, and n-C₃₋₆alkyl refers to a saturated, straight hydrocarbonchain having from 3 to 6 carbon atoms, such as n-propyl, and n-butyl.

It is to be understood that references herein to compounds of theinvention mean a compound of formula (I) as the free base, or as a salt,for example a pharmaceutically acceptable salt.

In one aspect of the invention, a compound of formula (I) is in the formof a free base.

Salts of the compounds of formula (I) include pharmaceuticallyacceptable salts and salts which may not be pharmaceutically acceptablebut may be useful in the preparation of compounds of formula (I) andpharmaceutically acceptable salts thereof. In one aspect of theinvention, a compound of formula (I) is in the form of apharmaceutically acceptable salt. Salts may be derived from certaininorganic or organic acids.

Examples of salts are pharmaceutically acceptable salts.Pharmaceutically acceptable salts include acid addition salts. For areview on suitable salts see Berge et al., J. Pharm. Sci., 66:1-19(1977).

Examples of pharmaceutically acceptable acid addition salts of acompound of formula (I) include inorganic acids such as, for example,hydrochloric acid, hydrobromic acid, orthophosphoric acid, nitric acid,phosphoric acid, or sulphuric acid, or with organic acids such as, forexample, methanesulphonic acid, ethanesulphonic acid, p-toluenesulphonicacid, acetic acid, propionic acid, lactic acid, citric acid, fumaricacid, malic acid, succinic acid, salicylic acid, maleic acid,glycerophosphoric acid, tartaric, benzoic, glutamic, aspartic,benzenesulphonic, naphthalenesulphonic such as 2-naphthalenesuphonic,hexanoic acid or acetylsalicylic acid.

The invention includes within its scope all possible stoichiometric andnon-stoichiometric forms of the salts of the compounds of formula (I).For example, a dimaleate or hemi-succinate salt of the compound offormula (I).

Salts may be formed using techniques well-known in the art, for exampleby precipitation from solution followed by filtration, or by evaporationof the solvent.

Typically, a pharmaceutically acceptable acid addition salt can beformed by reaction of a compound of formula (I) with a suitable acid(such as hydrobromic, hydrochloric, sulphuric, maleic,p-toluenesulphonic, methanesulphonic, naphthalenesulphonic or succinicacids), optionally in a suitable solvent such as an organic solvent, togive the salt which is usually isolated for example by crystallisationand filtration.

It will be appreciated that many organic compounds can form complexeswith solvents in which they are reacted or from which they areprecipitated or crystallised. These complexes are known as “solvates”.For example, a complex with water is known as a “hydrate”. Solvents withhigh boiling points and/or solvents with a high propensity to formhydrogen bonds such as water, ethanol, iso-propyl alcohol, and N-methylpyrrolidinone may be used to form solvates. Methods for theidentification of solvated include, but are not limited to, NMR andmicroanalysis. Solvates of the compounds of formula (I) are within thescope of the invention. As used herein, the term solvate encompassessolvates of both a free base compound as well as any salt thereof.

Certain of the compounds of the invention may contain chiral atomsand/or multiple bonds, and hence may exist in one or more stereoisomericforms. The present invention encompasses all of the stereoisomers of thecompounds of the invention, including optical isomers, whether asindividual stereoisomers or as mixtures thereof including racemicmodifications. Any stereoisomer may contain less than 10% by weight, forexample less than 5% by weight, or less than 0.5% by weight, of anyother stereoisomer. For example, any optical isomer may contain lessthan 10% by weight, for example less than 5% by weight, or less than0.5% by weight, of its antipode.

Certain of the compounds of the invention may exist in tautomeric forms.It will be understood that the present invention encompasses all of thetautomers of the compounds of the invention whether as individualtautomers or as mixtures thereof.

The compounds of the invention may be in crystalline or amorphous form.Furthermore, some of the crystalline forms of the compounds of theinvention may exist as polymorphs, all of which are included within thescope of the present invention. The most thermodynamically stablepolymorphic form or forms of the compounds of the invention are ofparticular interest.

Polymorphic forms of compounds of the invention may be characterised anddifferentiated using a number of conventional analytical techniques,including, but not limited to, X-ray powder diffraction (XRPD), infraredspectroscopy (IR), Raman spectroscopy, differential scanning calorimetry(DSC), thermogravimetric analysis (TGA) and solid-state nuclear magneticresonance (ssNMR).

The present invention also includes all suitable isotopic variations ofa compound of formula (I) or a pharmaceutically acceptable salt thereof.An isotopic variation of a compound of formula (I), or apharmaceutically acceptable salt thereof, is defined as one in which atleast one atom is replaced by an atom having the same atomic number butan atomic mass different from the atomic mass usually found in nature.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of hydrogen, carbon, nitrogen, oxygen,fluorine and chlorine such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ¹⁸F and³⁶Cl, respectively. Certain isotopic variations of a compound of formula(I) or a salt or solvate thereof, for example, those in which aradioactive isotope such as ³H or ¹⁴C is incorporated, are useful indrug and/or substrate tissue distribution studies. Tritiated, i.e., ³H,and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution withisotopes such as deuterium, i.e., ²H, may afford certain therapeuticadvantages resulting from greater metabolic stability, for example,increased in vivo half-life or reduced dosage requirements and hence maybe preferred in some circumstances. Isotopic variations of a compound offormula (I), or a pharmaceutically salt thereof, can generally beprepared by conventional procedures such as by the illustrative methodsor by the preparations described in the Examples hereafter usingappropriate isotopic variations of suitable reagents.

It will be appreciated from the foregoing that included within the scopeof the invention are solvates, hydrates, isomers and polymorphic formsof the compounds of formula (I) and salts and solvates thereof.

Compound Preparation

The compounds of formula (I) and salts thereof may be prepared by themethodology described hereinafter, constituting further aspects of thisinvention.

Accordingly, there is provided a process for the preparation of acompound of formula (I), which process comprises the deprotection of acompound of formula (II):

wherein R₁, R₂, and m are as hereinbefore defined for a compound offormula (I), R₄ is as defined hereinbefore for a compound of formula (I)or is a suitable protecting group, such as t-butoxycarbonyl (BOC), andR₅ is a suitable protecting group such as benzyloxymethyl (BOM),2-(trimethylsilyl)ethoxymethyl or p-toluenesufonyl and thereafter, ifrequired, preparing a salt of the compound so-formed.

For example, a compound of formula (II) wherein R₅ is BOM is dissolvedin a suitable solvent, for example methanol or ethanol, and passed overa suitable catalyst, for example 10% palladium on carbon in the presenceof hydrogen at a suitable temperature, for example 20-60° C. in anapparatus such as the Thales H-Cube™. The product (I) is isolated byremoval of the solvent and purification if required.

For example, a compound of formula (II) wherein R₄ is BOC is dissolvedin a suitable solvent, for example methanol, and treated with a solutionof hydrogen chloride in a suitable solvent, for example 1,4-dioxane, atambient temperature for a suitable period of time, for example 21 hourshours to give a compound of formula (II) where R₄=H which on removal ofR₅ as above would give a compound of formula (I) where R₄=H.

A compound of formula (II) may be prepared by reaction of a compound offormula (III):

wherein R₁, R₂, R₄, R₅ and m are as defined hereinbefore with hydrogenin the presence of a catalyst.

For example a compound of formula (III) is dissolved in a suitablesolvent for example methyl alcohol or ethyl alcohol, and passed over asuitable catalyst, for example 10% palladium on carbon, in the presenceof hydrogen at a suitable temperature, for example 20-60° C., insuitable flow hydrogenation apparatus such as the Thales H-Cube™. Theproduct (II) is isolated by removal of the solvent and purification ifrequired.

When the R₅ protecting group is the BOM group the reaction to reductionthe alkyne can result in the simultaneous removal of the protectinggroup to afford compounds of formula (I)

A compound of formula (III) may be prepared by reaction of a compound offormula (IV):

wherein R₁, R₂, and m are as hereinbefore defined for a compound offormula (I) with a suitable alkyl halide R₄—X wherein X is halo forexample chloro, bromo or iodo.

For example a compound of formula (IV) is dissolved in a suitablesolvent, for example N,N-dimethylformamide, and treated with a suitablebase, for example triethylamine, and the alkyl halide, R₄—X. Thereaction mixture is stirred at a suitable temperature, for example 20°C. for a suitable period of time, for example 95 hours. The product(III) is isolated after removal of the solvent and purification.

A compound of formula (IV) may be prepared by reaction of a compound offormula (V):

wherein R₁, R₂, and m are as hereinbefore defined for a compound offormula (I) with hydrogen chloride.

For example, a compound of formula (V) is dissolved in a suitablesolvent, for example methanol, and treated with a solution of hydrogenchloride in a suitable solvent, for example 1,4-dioxane, at ambienttemperature for a suitable period of time, for example 15 hours. Theproduct (IV) is isolated after removal of the solvent and purification.

A compound of formula (V) may be prepared by reaction of a compound offormula (VI):

wherein R₁ and R₂ are as hereinbefore defined for a compound of formula(I) and Y is a leaving group for example a halogen such as iodine orbromine or an alkyl sulfonate such as a trifluoromethane sulfonate witha compound of formula (VII).

wherein m is defined hereinbefore for a compound of formula (I).

For example a compound of formula (VI), a compound of formula (VII) aredissolved in a suitable solvent, for example DMF, in the presence ofcopper(I) iodide, a suitable catalyst, for examplebis(triphenylphosphine)palladium(II) dichloride and a suitable base, forexample triethylamine, and heated at a suitable temperature, for example20-55° C. for a suitable period of time, for example 0.5-17 hours. Theproduct is isolated after an aqueous work-up and purification.

Compounds of formula (VII) are either commercially available or may beprepared by methods described in the literature.

Compounds of formula (VI) may be prepared by reaction of compounds offormula (VIII):

wherein R₁, R₂ and R₅ are as defined hereinbefore and Y is defined for acompound of formula (VI) with a solution of ammonia.

For example a solution of aqueous ammonia (0.88) is added to a solutionof a compound of formula (VIII) in a suitable solvent, for exampleiso-propyl alcohol. The resultant mixture is then heated in a microwaveheater at a suitable temperature, for example 120-150° C. for a suitableperiod of time, for example 1-2 hours. The product is isolated after anaqueous work-up and purification.

Compounds of formula (VIII) may be prepared by reaction of compounds offormula (IX):

wherein R₁ and R₂ are as hereinbefore defined for a compound of formula(I) with a compound of formula (X):

wherein compound of formula (X) is a suitable precursor to theprotecting group R₅, such as benzyl chloromethyl ether or(2-(chloromethoxy)ethyl)trimethylsilane.

For example a compound of formula (IX) in a suitable solvent, forexample N,N-dimethylformamide or tetrahydrofuran, is treated with asuitable base, for example a suspension of sodium hydride in oil. Acompound of formula (X), for example benzyl chloromethyl ether or(2-(chloromethoxy)ethyl)trimethylsilane is added the reaction mixture isstirred at a suitable temperature, for example 20° C. for a suitableperiod of time, for example 1-4 hours. The product (IX) is isolatedafter an aqueous work-up and purification.

Compounds of formula (IX) may be prepared by reaction of compounds offormula (XI):

wherein R₁ and R₂ are as hereinbefore defined for a compound of formula(I) with a halogenating reagent, for example N-iodosuccinimide.

A compound of formula (XI) is dissolved in a suitable solvent, forexample tetrahydrofuran, is reacted with N-iodosuccinimide at suitabletemperature, for example 20° C. for a suitable period of time, forexample 1-2 hours. The product (X) is isolated after an aqueous work-upand purification.

Compounds of formula (XI) may be prepared by reaction of compounds offormula (XII):

wherein R₁ and R₂ are as hereinbefore defined for a compound of formula(I) with a chlorinating reagent, for example phosphorus oxychloride.

A compound of formula (XII) is suspended in phosphorus oxychloride andheated at a suitable temperature, for example 120° C. for a suitableperiod of time, for example 3-4 hours. Excess phosphorus oxychloride maybe removed in vacuo then the residue is poured onto ice and the pH ofthe mixture adjusted to 7-9. The product is then extracted into asuitable organic solvent, for example ethyl acetate. The product (XI) isisolated by removal of the solvent and purification if required.

Compounds of formula (XII) may be prepared by reaction of compounds offormula (XIII):

wherein R₁ and R₂ are as hereinbefore defined for a compound of formula(I) with a suitable base, for example sodium hydroxide.

A solution of compounds of formula (XIII) in a suitable solvent, forexample ethyl alcohol, is treated with an aqueous solution of sodiumhydroxide and the reaction mixture stirred at a suitable temperature,for example 80-100° C. for a suitable period of time, for example 4-18hours. The product (XII) is isolated after an aqueous work-up andpurification.

Compounds of formula (XIII) can be prepared by reaction of compounds offormula (XIV):

with compounds of formula (XV):

wherein R₁ and R₂ are as hereinbefore defined for a compound of formula(I).

For example a suspension of a compound of formula (XIV) in a compound offormula (XV) is treated with a solution of hydrogen chloride in asuitable solvent, for example a solution of hydrogen chloride in1,4-dioxane and is heated at a suitable temperature, 50-70° C. for asuitable period of time, for example 16-18 hours. The product (XIV) isisolated after filtration after the addition of a suitable solvent, forexample tert-butyl methyl ether.

Alternatively compound of formula (XII) can be prepared by reaction ofcompounds of formula (XIV) with compounds of formula (XVI):

wherein R₁ is as defined hereinbefore for a compound of formula (I).

For example a mixture of compounds of formula (XIV) and compounds offormula (XVI) are heated in a suitable solvent, for example o-xylene, ata suitable temperature, for example reflux, for a suitable period oftime, for example, 3 days. After cooling to ambient temperature theproduct is isolated after filtration.

Compounds of formula (X), formula (XIV), formula (XV) and formula (XVI)are either commercially available or may be prepared by methodsdescribed in the literature.

Methods of Use

Examples of disease states in which the compounds of formula (I) andpharmaceutically acceptable salts thereof have potentially beneficialeffects include allergic diseases and other inflammatory conditions forexample allergic rhinitis and asthma, infectious diseases, and cancer.The compounds of formula (I) and pharmaceutically acceptable saltsthereof are also of potential use as vaccine adjuvants.

As modulators of the immune response the compounds of formula (I) andpharmaceutically acceptable salts thereof may also be useful in thetreatment and/or prevention of immune-mediated disorders, including butnot limited to inflammatory or allergic diseases such as asthma,allergic rhinitis and rhinoconjuctivitis, food allergy, hypersensitivitylung diseases, eosinophilic pneumonitis, delayed-type hypersensitivitydisorders, atherosclerosis, pancreatitis, gastritis, colitis,osteoarthritis, psoriasis, sarcoidosis, pulmonary fibrosis, respiratorydistress syndrome, bronchiolitis, chronic obstructive pulmonary disease,sinusitis, cystic fibrosis, actinic keratosis, skin dysplasia, chronicurticaria, eczema and all types of dermatitis.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be useful in the treatment and/or prevention ofreactions against respiratory infections, including but not limited toairways viral exacerbations and tonsillitis. The compounds may also beuseful in the treatment and/or prevention of autoimmune diseasesincluding but not limited to rheumatoid arthritis, psoriatic arthritis,systemic lupus erythematosus, Sjöegrens disease, ankylosing spondylitis,scleroderma, dermatomyositis, diabetes, graft rejection, includinggraft-versus-host disease, inflammatory bowel diseases including, butnot limited to, Crohn's disease and ulcerative colitis.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be useful in the treatment of infectious diseasesincluding, but not limited to, those caused by hepatitis viruses (e.g.hepatitis B virus, hepatitis C virus), human immunodeficiency virus,papillomaviruses, herpesviruses, respiratory viruses (e.g. influenzaviruses, respiratory syncytial virus, rhinovirus, metapneumovirus,parainfluenzavirus, SARS), and West Nile virus. The compounds of formula(I) and pharmaceutically acceptable salts thereof may also be useful inthe treatment of microbial infections caused by, for example, bacteria,fungi, or protozoa. These include, but are not limited to, tuberculosis,bacterial pneumonia, aspergillosis, histoplasmosis, candidosis,pneumocystosis, leprosy, chlamydia, cryptococcal disease,cryptosporidosis, toxoplasmosis, leishmania, malaria, andtrypanosomiasis.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be useful in the treatment of various cancers, inparticular the treatment of cancers that are known to be responsive toimmunotherapy and including, but not limited to, renal cell carcinoma,lung cancer, breast cancer, colorectal cancer, bladder cancer, melanoma,leukaemia, lymphomas and ovarian cancer.

It will be appreciated by those skilled in the art that referencesherein to treatment or therapy may, depending on the condition, extendto prophylaxis as well as the treatment of established conditions.

There is thus provided as a further aspect of the invention a compoundof formula (I), or a pharmaceutically acceptable salt thereof, for usein therapy.

It will be appreciated that, when a compound of formula (I) or apharmaceutically acceptable salt thereof is used in therapy, it is usedas an active therapeutic agent.

There is also therefore provided a compound of formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofallergic diseases and other inflammatory conditions, infectiousdiseases, and cancer.

There is also therefore provided a compound of formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofallergic rhinitis.

There is also therefore provided a compound of formula (I), or apharmaceutically acceptable salt thereof, for use in the treatment ofasthma.

There is further provided the use of a compound of formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of allergic diseases and other inflammatoryconditions, infectious diseases, and cancer.

There is further provided the use of a compound of formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of allergic rhinitis.

There is further provided the use of a compound of formula (I), or apharmaceutically acceptable salt thereof, in the manufacture of amedicament for the treatment of asthma.

There is further provided a method of treatment of allergic diseases andother inflammatory conditions, infectious diseases, and cancer, whichmethod comprises administering to a human subject in need thereof, atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof.

There is further provided a method of treatment of allergic rhinitis,which method comprises administering to a human subject in need thereof,a therapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof.

There is further provided a method of treatment of asthma, which methodcomprises administering to a human subject in need thereof, atherapeutically effective amount of a compound of formula (I), or apharmaceutically acceptable salt thereof.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof are also of potential use as vaccine adjuvants.

There is thus provided as a further aspect of the invention a vaccinecomposition comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof, and an antigen or antigen composition for usein therapy.

There is thus provided as a further aspect of the invention the use of acompound of formula (I), or a pharmaceutically acceptable salt thereof,and an antigen or antigen composition in the manufacture of a medicamentfor use in therapy.

There is further provided a method of treating or preventing diseasecomprising the administration to a human subject suffering from orsusceptible to disease, a vaccine composition comprising a compound offormula (I), or a pharmaceutically acceptable salt thereof, and anantigen or antigen composition.

Compositions

The compounds of formula (I) and pharmaceutically acceptable saltsthereof will normally, but not necessarily, be formulated intopharmaceutical compositions prior to administration to a patient.Accordingly, in another aspect of the invention there is provided apharmaceutical composition comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be formulated for administration in any convenient way. Thecompounds of formula (I) and pharmaceutically acceptable salts thereofmay, for example, be formulated for oral, topical, inhaled, intranasal,buccal, parenteral (for example intravenous, subcutaneous, intradermal,or intramuscular) or rectal administration. In one aspect, the compoundsof formula (I) and pharmaceutically acceptable salts thereof areformulated for oral administration. In a further aspect, the compoundsof formula (I) and pharmaceutically acceptable salts thereof areformulated for topical administration, for example intranasal or inhaledadministration.

Tablets and capsules for oral administration may contain conventionalexcipients such as binding agents, for example syrup, acacia, gelatin,sorbitol, tragacanth, mucilage of starch, cellulose or polyvinylpyrrolidone; fillers, for example, lactose, microcrystalline cellulose,sugar, maize starch, calcium phosphate or sorbitol; lubricants, forexample, magnesium stearate, stearic acid, talc, polyethylene glycol orsilica; disintegrants, for example, potato starch, croscarmellose sodiumor sodium starch glycollate; or wetting agents such as sodium laurylsulphate. The tablets may be coated according to methods well known inthe art.

Oral liquid preparations may be in the form of, for example, aqueous oroily suspensions, solutions, emulsions, syrups or elixirs, or may bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations may contain conventionaladditives such as suspending agents, for example, sorbitol syrup, methylcellulose, glucose/sugar syrup, gelatin, hydroxymethyl cellulose,carboxymethyl cellulose, aluminium stearate gel or hydrogenated ediblefats; emulsifying agents, for example, lecithin, sorbitan mono-oleate oracacia; non-aqueous vehicles (which may include edible oils), forexample almond oil, fractionated coconut oil, oily esters, propyleneglycol or ethyl alcohol; or preservatives, for example, methyl or propylp-hydroxybenzoates or sorbic acid. The preparations may also containbuffer salts, flavouring, colouring and/or sweetening agents (e.g.mannitol) as appropriate.

Compositions for intranasal administration include aqueous compositionsadministered to the nose by drops or by pressurised pump. Suitablecompositions contain water as the diluent or carrier for this purpose.Compositions for administration to the lung or nose may contain one ormore excipients, for example one or more suspending agents, one or morepreservatives, one or more surfactants, one or more tonicity adjustingagents, one or more co-solvents, and may include components to controlthe pH of the composition, for example a buffer system. Further, thecompositions may contain other excipients such as antioxidants, forexample sodium metabisulphite, and taste-masking agents. Compositionsmay also be administered to the nose or other regions of the respiratorytract by nebulisation.

Intranasal compositions may permit the compound(s) of formula (I) or (a)pharmaceutically acceptable salt(s) thereof to be delivered to all areasof the nasal cavities (the target tissue) and further, may permit thecompound(s) of formula (I) or (a) pharmaceutically acceptable salt(s)thereof to remain in contact with the target tissue for longer periodsof time. A suitable dosing regime for intranasal compositions would befor the patient to inhale slowly through the nose subsequent to thenasal cavity being cleared. During inhalation the composition would beadministered to one nostril while the other is manually compressed. Thisprocedure would then be repeated for the other nostril. Typically, oneor two sprays per nostril would be administered by the above procedureone, two, or three times each day, ideally once daily. Of particularinterest are intranasal compositions suitable for once-dailyadministration.

The suspending agent(s), if included, will typically be present in anamount of from 0.1 to 5% (w/w), such as from 1.5% to 2.4% (w/w), basedon the total weight of the composition. Examples of pharmaceuticallyacceptable suspending agents include, but are not limited to, Avicel®(microcrystalline cellulose and carboxymethylcellulose sodium),carboxymethylcellulose sodium, veegum, tragacanth, bentonite,methylcellulose, xanthan gum, carbopol and polyethylene glycols.

Compositions for administration to the lung or nose may contain one ormore excipients may be protected from microbial or fungal contaminationand growth by inclusion of one or more preservatives. Examples ofpharmaceutically acceptable anti-microbial agents or preservativesinclude, but are not limited to, quaternary ammonium compounds (forexample benzalkonium chloride, benzethonium chloride, cetrimide,cetylpyridinium chloride, lauralkonium chloride and myristyl picoliniumchloride), mercurial agents (for example phenylmercuric nitrate,phenylmercuric acetate and thimerosal), alcoholic agents (for examplechlorobutanol, phenylethyl alcohol and benzyl alcohol), antibacterialesters (for example esters of para-hydroxybenzoic acid), chelatingagents such as disodium edetate (EDTA) and other anti-microbial agentssuch as chlorhexidine, chlorocresol, sorbic acid and its salts (such aspotassium sorbate) and polymyxin. Examples of pharmaceuticallyacceptable anti-fungal agents or preservatives include, but are notlimited to, sodium benzoate, sorbic acid, sodium propionate,methylparaben, ethylparaben, propylparaben and butylparaben. Thepreservative(s), if included, may be present in an amount of from 0.001to 1% (w/w), such as from 0.015% to 0.5% (w/w) based on the total weightof the composition.

Compositions (for example wherein at least one compound is insuspension) may include one or more surfactants which functions tofacilitate dissolution of the medicament particles in the aqueous phaseof the composition. For example, the amount of surfactant used is anamount which will not cause foaming during mixing. Examples ofpharmaceutically acceptable surfactants include fatty alcohols, estersand ethers, such as polyoxyethylene (20) sorbitan monooleate(Polysorbate 80), macrogol ethers, and poloxamers. The surfactant may bepresent in an amount of between about 0.01 to 10% (w/w), such as from0.01 to 0.75% (w/w), for example about 0.5% (w/w), based on the totalweight of the composition.

One or more tonicity-adjusting agent(s) may be included to achievetonicity with body fluids e.g. fluids of the nasal cavity, resulting inreduced levels of irritancy. Examples of pharmaceutically acceptabletonicity-adjusting agents include, but are not limited to, sodiumchloride, dextrose, xylitol, calcium chloride, glucose, glycerine andsorbitol. A tonicity-adjusting agent, if present, may be included in anamount of from 0.1 to 10% (w/w), such as from 4.5 to 5.5% (w/w), forexample about 5.0% (w/w), based on the total weight of the composition.

The compositions of the invention may be buffered by the addition ofsuitable buffering agents such as sodium citrate, citric acid,trometamol, phosphates such as disodium phosphate (for example thedodecahydrate, heptahydrate, dihydrate and anhydrous forms), or sodiumphosphate and mixtures thereof.

A buffering agent, if present, may be included in an amount of from 0.1to 5% (w/w), for example 1 to 3% (w/w) based on the total weight of thecomposition.

Examples of taste-masking agents include sucralose, sucrose, saccharinor a salt thereof, fructose, dextrose, glycerol, corn syrup, aspartame,acesulfame-K, xylitol, sorbitol, erythritol, ammonium glycyrrhizinate,thaumatin, neotame, mannitol, menthol, eucalyptus oil, camphor, anatural flavouring agent, an artificial flavouring agent, andcombinations thereof.

One or more co-solvent(s) may be included to aid solubility of themedicament compound(s) and/or other excipients. Examples ofpharmaceutically acceptable co-solvents include, but are not limited to,propylene glycol, dipropylene glycol, ethylene glycol, glycerol,ethanol, polyethylene glycols (for example PEG300 or PEG400), andmethanol. In one embodiment, the co-solvent is propylene glycol.

Co-solvent(s), if present, may be included in an amount of from 0.05 to30% (w/w), such as from 1 to 25% (w/w), for example from 1 to 10% (w/w)based on the total weight of the composition.

Compositions for inhaled administration include aqueous, organic oraqueous/organic mixtures, dry powder or crystalline compositionsadministered to the respiratory tract by pressurised pump or inhaler,for example, reservoir dry powder inhalers, unit-dose dry powderinhalers, pre-metered multi-dose dry powder inhalers, nasal inhalers orpressurised aerosol inhalers, nebulisers or insufflators. Suitablecompositions contain water as the diluent or carrier for this purposeand may be provided with conventional excipients such as bufferingagents, tonicity modifying agents and the like. Aqueous compositions mayalso be administered to the nose and other regions of the respiratorytract by nebulisation. Such compositions may be aqueous solutions orsuspensions or aerosols delivered from pressurised packs, such as ametered dose inhaler, with the use of a suitable liquefied propellant.

Compositions for administration topically to the nose (for example, forthe treatment of rhinitis) or to the lung, include pressurised aerosolcompositions and aqueous compositions delivered to the nasal cavities bypressurised pump. Compositions which are non-pressurised and aresuitable for administration topically to the nasal cavity are ofparticular interest. Suitable compositions contain water as the diluentor carrier for this purpose. Aqueous compositions for administration tothe lung or nose may be provided with conventional excipients such asbuffering agents, tonicity-modifying agents and the like. Aqueouscompositions may also be administered to the nose by nebulisation.

A fluid dispenser may typically be used to deliver a fluid compositionto the nasal cavities. The fluid composition may be aqueous ornon-aqueous, but typically aqueous. The compound of formula (I), or apharmaceutically acceptable salt thereof, may be formulated as asuspension or solution. Such a fluid dispenser may have a dispensingnozzle or dispensing orifice through which a metered dose of the fluidcomposition is dispensed upon the application of a user-applied force toa pump mechanism of the fluid dispenser. Such fluid dispensers aregenerally provided with a reservoir of multiple metered doses of thefluid composition, the doses being dispensable upon sequential pumpactuations. Alternatively, the fluid dispenser for delivery of a fluidcomposition to the nasal cavities may be designed to be dose-limited,for example a single use dispenser comprising a single dose. Thedispensing nozzle or orifice may be configured for insertion into thenostrils of the user for spray dispensing of the fluid composition intothe nasal cavity. A fluid dispenser of the aforementioned type isdescribed and illustrated in International Patent Applicationpublication number WO 2005/044354 (Glaxo Group Limited). The dispenserhas a housing which houses a fluid-discharge device having a compressionpump mounted on a container for containing a fluid composition. Thehousing has at least one finger-operable side lever which is movableinwardly with respect to the housing to move the container upwardly inthe housing by means of a cam to cause the pump to compress and pump ametered dose of the composition out of a pump stem through a nasalnozzle of the housing. In one embodiment, the fluid dispenser is of thegeneral type illustrated in FIGS. 30-40 of WO 2005/044354.

Aqueous compositions containing a compound of formula (I) or apharmaceutically acceptable salt thereof may also be delivered by a pumpas disclosed in International Patent Application publication numberWO2007/138084 (Glaxo Group Limited), for example as disclosed withreference to FIGS. 22-46 thereof, or as disclosed in United Kingdompatent application number GB0723418.0 (Glaxo Group Limited), for exampleas disclosed with reference to FIGS. 7-32 thereof. The pump may beactuated by an actuator as disclosed in FIGS. 1-6 of GB0723418.0.

Dry powder compositions for topical delivery to the lung by inhalationmay, for example, be presented in capsules and cartridges of for examplegelatine, or blisters of for example laminated aluminium foil, for usein an inhaler or insufflator. Powder blend compositions generallycontain a powder mix for inhalation of the compound of formula (I) or apharmaceutically acceptable salt thereof and a suitable powder base(carrier/diluent/excipient substance) such as mono-, di-, orpolysaccharides (for example lactose or starch). Dry powder compositionsmay also include, in addition to the drug and carrier, a furtherexcipient (for example a ternary agent such as a sugar ester for examplecellobiose octaacetate, calcium stearate, or magnesium stearate.

In one embodiment, a composition suitable for inhaled administration maybe incorporated into a plurality of sealed dose containers provided onmedicament pack(s) mounted inside a suitable inhalation device. Thecontainers may be rupturable, peelable, or otherwise openableone-at-a-time and the doses of the dry powder composition administeredby inhalation on a mouthpiece of the inhalation device, as known in theart. The medicament pack may take a number of different forms, forinstance a disk-shape or an elongate strip. Representative inhalationdevices are the DISKHALER™ and DISKUS™ devices, marketed byGlaxoSmithKline.

A dry powder inhalable composition may also be provided as a bulkreservoir in an inhalation device, the device then being provided with ametering mechanism for metering a dose of the composition from thereservoir to an inhalation channel where the metered dose is able to beinhaled by a patient inhaling at a mouthpiece of the device. Exemplarymarketed devices of this type are TURBUHALER™ (AstraZeneca), TWISTHALER™(Schering) and CLICKHALER™ (Innovata.)

A further delivery method for a dry powder inhalable composition is formetered doses of the composition to be provided in capsules (one doseper capsule) which are then loaded into an inhalation device, typicallyby the patient on demand. The device has means to rupture, pierce orotherwise open the capsule so that the dose is able to be entrained intothe patient's lung when they inhale at the device mouthpiece. Asmarketed examples of such devices there may be mentioned ROTAHALER™(GlaxoSmithKline) and HANDIHALER™ (Boehringer Ingelheim.)

Pressurised aerosol compositions suitable for inhalation can be either asuspension or a solution and may contain a compound of formula (I) or apharmaceutically acceptable salt thereof and a suitable propellant suchas a fluorocarbon or hydrogen-containing chlorofluorocarbon or mixturesthereof, particularly hydrofluoroalkanes, especially1,1,1,2-tetrafluoroethane, 1,1,1,2,3,3,3-heptafluoro-n-propane or amixture thereof. The aerosol composition may optionally containadditional composition excipients well known in the art such assurfactants e.g. oleic acid, lecithin or an oligolactic acid orderivative thereof e.g. as described in WO 94/21229 and WO 98/34596(Minnesota Mining and Manufacturing Company) and co-solvents e.g.ethanol. Pressurised compositions will generally be retained in acanister (e.g. an aluminium canister) closed with a valve (e.g. ametering valve) and fitted into an actuator provided with a mouthpiece.

Ointments, creams and gels, may, for example, be formulated with anaqueous or oily base with the addition of suitable thickening and/orgelling agent and/or solvents. Such bases may thus, for example, includewater and/or an oil such as liquid paraffin or a vegetable oil such asarachis oil or castor oil, or a solvent such as polyethylene glycol.Thickening agents and gelling agents which may be used according to thenature of the base include soft paraffin, aluminium stearate,cetostearyl alcohol, polyethylene glycols, wool-fat, beeswax, carboxypolymethylene and cellulose derivatives, and/or glycerylmonostearate and/or non-ionic emulsifying agents.

Lotions may be formulated with an aqueous or oily base and will ingeneral also contain one or more emulsifying agents, stabilising agents,dispersing agents, suspending agents or thickening agents.

Powders for external application may be formed with the aid of anysuitable powder base, for example, talc, lactose or starch. Drops may beformulated with an aqueous or non-aqueous base also comprising one ormore dispersing agents, solubilising agents, suspending agents orpreservatives.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may, for example, be formulated for transdermal delivery bycomposition into patches or other devices (e.g. pressurised gas devices)which deliver the active component into the skin.

For buccal administration the compositions may take the form of tabletsor lozenges formulated in the conventional manner.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be formulated as suppositories, e.g. containingconventional suppository bases such as cocoa butter or other glycerides.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be formulated for parenteral administration by bolusinjection or continuous infusion and may be presented in unit dose form,for instance as ampoules, vials, small volume infusions or pre-filledsyringes, or in multidose containers with an added preservative.

The compositions may take such forms as solutions, suspensions, oremulsions in aqueous or non-aqueous vehicles, and may containformulatory agents such as antioxidants, buffers, antimicrobial agentsand/or tonicity adjusting agents. Alternatively, the active ingredientmay be in powder form for constitution with a suitable vehicle, e.g.sterile, pyrogen-free water, before use. The dry solid presentation maybe prepared by filling a sterile powder aseptically into individualsterile containers or by filling a sterile solution aseptically intoeach container and freeze-drying.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may also be formulated with vaccines as adjuvants to modulatetheir activity. Such compositions may contain antibody(ies) or antibodyfragment(s) or an antigenic component including but not limited toprotein, DNA, live or dead bacteria and/or viruses or virus-likeparticles, together with one or more components with adjuvant activityincluding but not limited to aluminium salts, oil and water emulsions,heat shock proteins, lipid A preparations and derivatives, glycolipids,other TLR agonists such as CpG DNA or similar agents, cytokines such asGM-CSF or IL-12 or similar agents.

In a further aspect of the invention, there is provided a vaccineadjuvant comprising a compound of formula (I), or a pharmaceuticallyacceptable salt thereof.

There is further provided a vaccine composition comprising a compound offormula (I), or a pharmaceutically acceptable salt thereof, and anantigen or antigen composition.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be employed alone or in combination with othertherapeutically-active agents. The invention provides in a furtheraspect, a combination comprising a compound of formula (I), or apharmaceutically acceptable salt thereof, together with at least oneother therapeutically-active agent.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof and the other therapeutically-active agent(s) may beadministered together or separately and, when administered separately,administration may occur simultaneously or sequentially, in any order.The amounts of the compound(s) of formula (I) or (a) pharmaceuticallyacceptable salt(s) thereof and the other therapeutically-active agent(s)and the relative timings of administration will be selected in order toachieve the desired combined therapeutic effect. The administration of acombination of a compound of formula (I) or a pharmaceuticallyacceptable salt thereof with other treatment agents may be byadministration concomitantly in a unitary pharmaceutical compositionincluding both compounds, or in separate pharmaceutical compositionseach including one of the compounds. Alternatively, the combination maybe administered separately in a sequential manner wherein one treatmentagent is administered first and the other second or vice versa. Suchsequential administration may be close in time or remote in time.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be used in combination with one or more agents useful in theprevention or treatment of viral infections. Examples of such agentsinclude, without limitation; polymerase inhibitors such as thosedisclosed in WO 2004/037818-A1, as well as those disclosed in WO2004/037818 and WO 2006/045613; JTK-003, JTK-019, NM-283, HCV-796,R-803, R1728, R1626, as well as those disclosed in WO 2006/018725, WO2004/074270, WO 2003/095441, US2005/0176701, WO 2006/020082, WO2005/080388, WO 2004/064925, WO 2004/065367, WO 2003/007945, WO02/04425, WO 2005/014543, WO 2003/000254, EP 1065213, WO 01/47883, WO2002/057287, WO 2002/057245 and similar agents; replication inhibitorssuch as acyclovir, famciclovir, ganciclovir, cidofovir, lamivudine andsimilar agents; protease inhibitors such as the HIV protease inhibitorssaquinavir, ritonavir, indinavir, nelfinavir, amprenavir, fosamprenavir,brecanavir, atazanavir, tipranavir, palinavir, lasinavir, and the HCVprotease inhibitors BILN2061, VX-950, SCHSO3034; and similar agents;nucleoside and nucleotide reverse transcriptase inhibitors such aszidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidine,adefovir, adefovir dipivoxil, fozivudine, todoxil, emtricitabine,alovudine, amdoxovir, elvucitabine, and similar agents; non-nucleosidereverse transcriptase inhibitors (including an agent havinganti-oxidation activity such as immunocal, oltipraz etc.) such asnevirapine, delavirdine, efavirenz, loviride, immunocal, oltipraz,capravirine, TMC-278, TMC-125, etravirine, and similar agents; entryinhibitors such as enfuvirtide (T-20), T-1249, PRO-542, PRO-140,TNX-355, BMS-806, 5-Helix and similar agents; integrase inhibitors suchas L-870,180 and similar agents; budding inhibitors such as PA-344 andPA-457, and similar agents; chemokine receptor inhibitors such asvicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK-427,857), TAK449, aswell as those disclosed in WO 02/74769, WO 2004/054974, WO 2004/055012,WO 2004/055010, WO 2004/055016, WO 2004/055011, and WO 2004/054581, andsimilar agents; neuraminidase inhibitors such as CS-8958, zanamivir,oseltamivir, peramivir and similar agents; ion channel blockers such asamantadine or rimantadine and similar agents; and interfering RNA andantisense oligonucleotides and such as ISIS-14803 and similar agents;antiviral agents of undetermined mechanism of action, for example thosedisclosed in WO 2005/105761, WO 2003/085375, WO 2006/122011, ribavirin,and similar agents. The compounds of formula (I) and pharmaceuticallyacceptable salts thereof may also be used in combination with one ormore other agents which may be useful in the prevention or treatment ofviral infections for example immune therapies (e.g. interferon or othercytokines/chemokines, cytokine/chemokine receptor modulators, cytokineagonists or antagonists and similar agents); and therapeutic vaccines,antifibrotic agents, anti-inflammatory agents such as corticosteroids orNSAIDs (non-steroidal anti-inflammatory agents) and similar agents.

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be used in combination with one or more other agents whichmay be useful in the prevention or treatment of allergic disease,inflammatory disease, autoimmune disease, for example; antigenimmunotherapy, anti-histamines, steroids, NSAIDs, bronchodilators (e.g.beta 2 agonists, adrenergic agonists, anticholinergic agents,theophylline), methotrexate, leukotriene modulators and similar agents;monoclonal antibody therapy such as anti-IgE, anti-TNF, anti-IL-5,anti-IL-6, anti-IL-12, anti-IL-1 and similar agents; receptor therapiese.g. entanercept and similar agents; antigen non-specificimmunotherapies (e.g. interferon or other cytokines/chemokines,cytokine/chemokine receptor modulators, cytokine agonists orantagonists, TLR agonists and similar agents).

The compounds of formula (I) and pharmaceutically acceptable saltsthereof may be used in combination with one or more other agents whichmay be useful in the prevention or treatment of cancer, for examplechemotherapeutics such as alkylating agents, topoisomerase inhibitors,antimetabolites, antimitotic agents, kinase inhibitors and similaragents; monoclonal antibody therapy such as trastuzumab, gemtuzumab andother similar agents; and hormone therapy such as tamoxifen, goserelinand similar agents.

The pharmaceutical compositions according to the invention may also beused alone or in combination with at least one other therapeutic agentin other therapeutic areas, for example gastrointestinal disease. Thecompositions according to the invention may also be used in combinationwith gene replacement therapy.

The invention includes in a further aspect a combination comprising acompound of formula (I), or a pharmaceutically acceptable salt thereof,together with at least one other therapeutically active agent.

The combinations referred to above may conveniently be presented for usein the form of a pharmaceutical composition and thus pharmaceuticalcompositions comprising a combination as defined above together with atleast one pharmaceutically acceptable diluent or carrier thereofrepresent a further aspect of the invention.

A therapeutically effective amount of a compound of formula (I) or apharmaceutically acceptable salt thereof will depend upon a number offactors. For example, the species, age, and weight of the recipient, theprecise condition requiring treatment and its severity, the nature ofthe composition, and the route of administration are all factors to beconsidered. The therapeutically effective amount ultimately should be atthe discretion of the attendant physician. Regardless, an effectiveamount of a compound of the present invention for the treatment ofhumans suffering from frailty, generally, should be in the range of0.0001 to 100 mg/kg body weight of recipient per day. More usually theeffective amount should be in the range of 0.001 to 10 mg/kg body weightper day. Thus, for a 70 kg adult one example of an actual amount per daywould usually be from 7 to 700 mg. For intranasal and inhaled routes ofadministration, typical doses for a 70 kg adult should be in the rangeof 0.1 micrograms to 1 mg per day, for example 1 μg, 10 μg or 100 μg.This amount may be given in a single dose per day or in a number (suchas two, three, four, five, or more) of sub-doses per day such that thetotal daily dose is the same. An effective amount of a pharmaceuticallyacceptable salt of a compound of formula (I) may be determined as aproportion of the effective amount of the compound of formula (I) or apharmaceutically acceptable salt thereof per se. Similar dosages shouldbe appropriate for treatment of the other conditions referred to herein.

Compounds of formula (I) and pharmaceutically acceptable salts thereofmay also be administered at any appropriate frequency e.g. 1-7 times perweek. The precise dosing regimen will of course depend on factors suchas the therapeutic indication, the age and condition of the patient, andthe particular route of administration chosen. In one aspect of theinvention, a compound of formula (I), or a pharmaceutically acceptablesalt thereof, may be administered once weekly for a period of 4 to 8weeks, for example 4, 5, 6, 7 or 8 weeks.

Pharmaceutical compositions may be presented in unit-dose formscontaining a predetermined amount of active ingredient per unit dose.Such a unit may contain, as a non-limiting example, 0.5 mg to 1 g of acompound of formula (I) or a pharmaceutically acceptable salt thereof,depending on the condition being treated, the route of administration,and the age, weight, and condition of the patient. Preferred unit-dosagecompositions are those containing a daily dose or sub-dose, as hereinabove recited, or an appropriate fraction thereof, of an activeingredient. Such pharmaceutical compositions may be prepared by any ofthe methods well-known in the pharmacy art.

There is also provided a process for preparing such a pharmaceuticalcomposition which comprises admixing a compound of formula (I), or apharmaceutically acceptable salt thereof, with one or morepharmaceutically acceptable excipients.

Aspects of the invention are illustrated by reference to, but are in noway limited by, the following Examples.

ABBREVIATIONS

The following list provides definitions of certain abbreviations as usedherein. It will be appreciated that the list is not exhaustive, but themeaning of those abbreviations not herein below defined will be readilyapparent to those skilled in the art.

DCM Dichloromethane DMF N,N-Dimethylformamide DMSO DimethylsulphoxideDME 1,2-Dimethoxyethane THF Tetrahydrofuran

EtOAc Ethyl acetate

MeOH Methanol EtOH Ethanol MeCN Acetonitrile

HCl Hydrochloric acidHPLC High performance liquid chromatography

MDAP Mass Directed Autopreparative HPLC

SPE Solid phase extraction

MeOH Methanol

TFA Trifluoroacetic acid

DIPEA N,N-Diisopropylethylamine Experimental Details ¹H NMR

¹H NMR spectra were recorded in either CDCl₃ or DMSO-d₆on either aBruker DPX 400 or Bruker Avance DRX, Varian Unity 400 spectrometer orJEOL Delta all working at 400 MHz. The internal standard used was eithertetramethylsilane or the residual protonated solvent at 7.25 ppm forCDCl₃ or 2.50 ppm for DMSO-d₆.

LCMS System A

Column: 50 mm×2.1 mm ID, 1.7 μm Acquity UPLC BEH C₁₈

Flow Rate: 1 mL/min.

Temp: 40° C.

UV detection range: 210 to 350 nm

Mass spectrum: Recorded on a mass spectrometer using alternative-scanpositive and negative mode electrospray ionisation

Solvents: A: 0.1% v/v formic acid in water

-   -   B: 0.1% v/v formic acid acetonitrile

Gradient:

Time (min.) A % B % 0 97 3 1.5 0 100 1.9 0 100 2.0 97 3

System B

Column: 50 mm×2.1 mm ID, 1.7 μm Acquity UPLC BEH C₁₈

Flow Rate: 1 mL/min.

Temp: 40° C.

UV detection range: 210 to 350 nm

Mass spectrum: Recorded on a mass spectrometer using alternative-scanpositive and negative mode electrospray ionisation

-   Solvents: A: 10 mM ammonium bicarbonate in water adjusted to pH10    with ammonia solution    -   B: acetonitrile

Gradient:

Time (min.) A % B % 0 99 1 1.5 3 97 1.9 3 97 2.0 0 100

Mass Directed Autopreparative HPLC (MDAP)

Mass directed autopreparative HPLC was undertaken under the conditionsgiven below. The UV detection was an averaged signal from wavelength of210 nm to 350 nm and mass spectra were recorded on a mass spectrometerusing alternate-scan positive and negative mode electrospray ionization.

Method A Method A was conducted on a Sunfire C₁₈ column (typically 150mm×30 mm i.d. 5 μm packing diameter) at ambient temperature. Thesolvents employed were:A=0.1% v/v solution of formic acid in waterB=0.1% v/v solution of formic acid in acetonitrile.

Method B

Method B was conducted on an XBridge C₁₈ column (typically 100 mm×30 mmi.d. 5 μm packing diameter) at ambient temperature. The solventsemployed were:

A=10 mM aqueous ammonium bicarbonate adjusted to pH 10 with ammoniasolution.B=acetonitrile.

Method C

Method C was conducted on a Sunfire C₁₈ column (typically 150 mm×30 mmi.d. 5 μm packing diameter) at ambient temperature. The solventsemployed were:

A=0.1% v/v solution of trifluoroacetic acid in waterB=0.1% v/v solution of trifluoroacetic acid in acetonitrile.

Intermediate Preparation Intermediate 1: Ethyl3-pentanimidamido-1H-pyrrole-2-carboxylate hydrochloride

A solution of hydrogen chloride in dioxane (12 mL, 4M, 48 mmol) wasadded dropwise to a suspension of ethyl 3-amino-1H-pyrrole-2-carboxylatehydrochloride (2.04 g, 10.7 mmol) (J. Org. Chem. 1999, 64(22), 8411) invaleronitrile (30 mL). The resultant mixture was heated at 50° C. for 18hours. The reaction mixture was cooled to room temperature and the solidmaterial collected by filtration and washed with TBME. The titlecompound was obtained as an off-white solid (2.19 g). A further portionof TBME was added to the filtrate and the mixture re-filtered, theprecipitate was washed with TBME and dried to give an additional portionof the title compound (0.275 g).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 12.22 (br. s., 1H) 10.88 (s, 1H) 9.39(br. s., 1H) 8.25 (br. s., 1H) 7.09 (t, J=2.9 Hz, 1H) 6.19 (t, J=2.5 Hz,1H) 4.23 (q, 1=7.0 Hz, 2H) 2.52-2.60 (m, 2H) 1.63-1.77 (m, 2H) 1.34-1.47(m, 2H) 1.27 (t, J=7.2 Hz, 3H) 0.94 (t, J=7.4 Hz, 3H)

Intermediate 2: 2-Butyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one

A solution of sodium hydroxide (1.44 g, 35.9 mmol) in water (7 mL) wasadded to a solution of ethyl 3-pentanimidamido-1H-pyrrole-2-carboxylatehydrochloride (2.46 g, 8.99 mmol) in ethanol (30 mL). The resultantmixture was heated at reflux for a total of 4 hours. The reactionmixture was cooled to room temperature and the pH adjusted to pH 6.5with aqueous citric acid. The resultant mixture was extracted with ethylacetate (2×50 mL). The combined organic phases were washed withsaturated aqueous sodium chloride solution, dried (Na₂SO₄), filtered andevaporated to give the title compound as a pale brown solid (1.69 g).

LCMS (System B): t_(RET)=0.66 min; MH⁺ 192

Intermediate 3: 2-Butyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine

Phosphorus oxychloride (20 mL, 21.46 mmol) was added to2-butyl-3H-pyrrolo[3,2-d]pyrimidin-4(5H)-one (1.69 g). The resultantmixture was heated at 100° C. After 4 hours the reaction mixture wascooled to room temperature then poured onto ice. The aqueous phase wastreated with aqueous sodium hydroxide solution (5M) until the pH was 7.The resultant mixture was extracted with ethyl acetate (2×150 mL). Thecombined organic phase were washed with brine, dried (Na₂SO₄), filteredand evaporated to give the title compound (1.69 g)

LCMS (System B): t_(RET)=0.90 min; MH⁺ 210, 212

Intermediate 4: 2-Butyl-4-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine

N-Iodosuccinimide (2.09 g, 9.29 mmol) was added portionwise to a stirredsolution of 2-butyl-4-chloro-5H-pyrrolo[3,2-d]pyrimidine (1.69 g, 8.06mmol) in THF (35 mL). The resultant mixture was stirred at roomtemperature for 1 hour. The reaction mixture was diluted with TBME (50mL) then washed with aqueous sodium thiosulphate solution (50 mL) thensaturated aqueous sodium chloride solution (20 mL). The organic phasewas dried (Na₂SO₄), filtered and evaporated. The sample was dissolved indichloromethane and purified by chromatography on silica using agradient of 0-100% dichloromethane-cyclohexane over 30 minutes followedby a gradient of 0-100% TBME-cyclohexane followed by 0-20% methanol over15 minutes. The appropriate fractions were identified by LC-MS thencombined and evaporated in vacuo to give the title compound as a yellowsolid (2.2 g).

LCMS (System B): t_(RET)=1.14 min; MH⁺ 336, 338

Intermediate 5:5-((Benzyloxy)methyl)-2-butyl-4-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine

Sodium hydride (0.338 g, 60% in oil, 14.08 mmol) was added portionwiseto a stirred solution of4-chloro-7-iodo-2-butyl-5H-pyrrolo[3,2-d]pyrimidine (2.19 g, 6.53 mmol)in DMF (30 mL) cooled in an ice-bath. After 30 minutes benzylchloromethyl ether (1.13 mL, 1.278 g, 8.16 mmol) was added and thereaction stirred at room temperature. The reaction mixture was quenchedwith water and the resultant mixture partitioned between ethyl acetate(150 mL) and water (150 mL). The organic phase was washed with waterthen saturated aqueous sodium chloride solution, dried (Na₂SO₄),filtered and evaporated. The sample was dissolved in dichloromethane andpurified by chromatography on silica (100 g) using a gradient of 0-100%ethyl acetate-cyclohexane over 30 minutes. The appropriate fractionswere combined and evaporated in vacuo to give the title compound as ayellow oil (2.82 g).

LCMS (System B): t_(RET)=1.49 min; MH⁺ 456, 458

Intermediate 6:5-((Benzyloxy)methyl)-2-butyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine

5-((Benzyloxy)methyl)-2-butyl-4-chloro-7-iodo-5H-pyrrolo[3,2-d]pyrimidine(1 g, 2.2 mmol) was suspended in 2-propanol (5 mL) and 35% (0.88)ammonia solution (4 mL). The reaction was stirred at 120° C. for 90minutes in a Biotage Initiator microwave. A further 1 mL of 35% (0.88)ammonia solution was added to the reaction. The reaction was stirred at120° C. for 90 minutes in a Biotage Initiator microwave. The reactionwas evaporated in vacuo to yield a pale yellow oil. The oil wasdissolved in the minimum volume of 20% methanol in dichloromethane andpurified by chromatography on silica using a gradient of 0-100% ethylacetate in cyclohexane gradient over 80 minutes. Fractions were combinedand evaporated in vacuo to yield the title compound as a colourless oil(768 mg).

LCMS (System B): t_(RET)=1.19 min; MH⁺ 437

Intermediate 7: tert-Butyl 4-(prop-2-yn-1-yl)piperidine-1-carboxylate

To a solution of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (383mg, 1.685 mmol) in anhydrous methanol (6 mL) was added potassiumcarbonate (466 mg, 3.37 mmol) and the suspension was stirred at roomtemperature for 5 minutes. Dimethyl (1-diazo-2-oxopropyl)phosphonate(388 mg, 2.022 mmol) was then added and the reaction was stirred at roomtemperature for 17 hours. The reaction was partitioned between diethylether and saturated aqueous sodium hydrogencarbonate solution. Theorganic phase was separated, passed through a hydrophobic frit andevaporated in vacuo to yield a yellow oil. The crude material was loadedonto a 10 g isolute silica cartridge in the minimum volume of ethylacetate and eluted with ethyl acetate (40 mL). The ethyl acetate eluentwas evaporated in vacuo to yield the title compound as a colourless oil(294 mg).

¹H NMR (400 MHz, CDCl₃) δ ppm 4.00-4.20 (m, 2H) 2.61-2.78 (m, 2H)2.10-2.20 (m, 2H) 1.93-2.01 (m, 1H) 1.56-1.81 (m, 4H) 1.46 (s, 9H)1.11-1.29 (m, 2H)

Intermediate 8: tert-Butyl4-(3-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)prop-2-yn-1-yl)piperidine-1-carboxylate

To a degassed solution of5-((benzyloxy)methyl)-2-butyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amine(319 mg, 0.731 mmol) in anhydrous N,N-dimethylformamide (5 mL) undernitrogen atmosphere at room temperature was added copper(I) iodide (27mg, 0.142 mmol), bis(triphenylphosphine)palladium(II)dichloride (56 mg,0.08 mmol) and finally triethylamine (0.183 ml, 1.316 mmol). The mixturewas stirred at room temperature under a nitrogen atmosphere for 10minutes and then a solution of tert-butyl4-(prop-2-yn-1-yl)piperidine-1-carboxylate (294 mg, 1.317 mmol) inanhydrous degassed N,N-dimethylformamide (1 mL) was added. The reactionmixture was stirred at 55° C. for 40 minutes. The reaction wasevaporated in vacuo to yield a dark yellow oil. The oil was partitionedbetween water and dichloromethane. The organic layer was separated andthe aqueous back extracted with dichloromethane. The combined organicextracts were passed through a hydrophobic frit and evaporated in-vacuoto yield a dark yellow oil. The oil was dissolved in MeOH:DMSO (1:1)(4×1 mL) and purified by MDAP (Method B). Appropriate fractions werecombined and evaporated in-vacuoto yield the title compound as a paleyellow solid (212 mg)

LCMS (System B): t_(RET)=1.41 min; MH⁺ 532

Intermediate 9:5-((Benzyloxy)methyl)-2-butyl-7-(3-(piperidin-4-yl)prop-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a solution of tert-butyl4-(3-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)prop-2-yn-1-yl)piperidine-1-carboxylate(130 mg, 0.245 mmol) in anhydrous methanol (5 mL) was added 4M hydrogenchloride in 1,4-dioxane (0.306 mL, 1.223 mmol). The reaction was stirredat room temperature for 15 hours. The reaction was evaporated to drynessunder a stream of nitrogen to yield a yellow oil. The oil was dissolvedin MeOH:DMSO (1:1) (2×1 mL) and purified by MDAP (Method B). Appropriatefractions were combined and evaporated in vacuo to yield the titlecompound a pale yellow oil (64 mg).

LCMS (System B): t_(RET)=1.08 min; MH⁺ 432

Intermediate 10:5-((Benzyloxy)methyl)-2-butyl-7-(3-(1-isopropylpiperidin-4-yl)prop-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

To a solution of5-((benzyloxy)methyl)-2-butyl-7-(3-(piperidin-4-yl)prop-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(64 mg, 0.148 mmol) in anhydrous N,N-dimethylformamide (2 mL) at roomtemperature was added triethylamine (41 L, 0.294 mmol) and 2-iodopropane(18 L, 0.18 mmol). The reaction was stirred at room temperature for afurther 95 hours. The reaction was evaporated in vacuo to yield a yellowoil. The oil was dissolved in MeOH:DMSO (1:1) (1 mL) and purified byMDAP (Method B). Appropriate fractions were combined and evaporatedin-vacuoto yield the title compound as a pale yellow oil (31 mg).

LCMS (System B): t_(RET)=1.22 min; MH⁺ 474

Intermediate 11: tert-Butyl4-((4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)ethynyl)piperidine-1-carboxylate

Prepared similarly to Intermediate 8 from5-((benzyloxy)methyl)-2-butyl-7-iodo-5H-pyrrolo[3,2-d]pyrimidin-4-amineand tert-butyl 4-ethynylpiperidine-1-carboxylate (J. Med. Chem. 2004,47, 3111).

LCMS (System B): t_(RET)=1.38 min; MH⁺ 518

Example Preparation Example 12-Butyl-7-(3-(piperidin-4-yl)propyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amineformate

tert-Butyl4-(3-(4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)prop-2-yn-1-yl)piperidine-1-carboxylate(82 mg, 0.154 mmol) in ethanol (20 mL) was passed through the H-cube(settings: 20° C., full hydrogen, 1 mL/min flow rate and 10% palladiumon carbon CatCart30 as the catalyst). A new 10% palladium on carbonCatCart30 cartridge was inserted into the H-cube and the solution waspassed through the H-cube (settings: 45° C., full hydrogen, 1 mL/minflow rate). The solution was passed through the H-cube again then thesolution was evaporated in-vacuo to yield a white solid. The solid wasdissolved in MeOH:DMSO (1:1) (2×1 mL) and purified by MDAP (Method B).Appropriate fractions were combined and evaporated in-vacuo to yield awhite solid (19 mg). The solid was dissolved in anhydrous methanol (1.5mL) and 4M hydrogen chloride in 1,4-dioxane (0.114 mL, 0.456 mmol) andstirred at room temperature for 21 hours. The reaction was evaporated todryness under a stream of nitrogen to yield a brown oil. The oil wasdissolved in MeOH:DMSO (1:1) (1 mL) and purified by MDAP (Method A) Theappropriate fraction was evaporated in vacuo to yield the title compounda colourless oil (14.4 mg).

LCMS (System B): t_(RET)=0.82 min; MH⁺ 316

Example 22-Butyl-7-(3-(1-isopropylpiperidin-4-yl)propyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

5-((Benzyloxy)methyl)-2-butyl-7-(3-(1-isopropylpiperidin-4-yl)prop-1-yn-1-yl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine(31 mg, 0.065 mmol) in ethanol (10 mL) was passed through the H-cube(settings: 45° C., full hydrogen, 1 mL/min flow rate and 10% palladiumon carbon CatCart30 as the catalyst). The solution was evaporated undera stream of nitrogen to yield a white solid. The solid was dissolved inMeOH:DMSO (1:1) (1 mL) and purified by MDAP (Method B). The appropriatefraction was evaporated in-vacuo to yield the title compound as a whitesolid (8 mg)

LCMS (System B): t_(RET)=0.91 min; MH⁺ 358

Example 32-Butyl-7-(2-(piperidin-4-yl)ethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine

A solution of tert-butyl4-((4-amino-5-((benzyloxy)methyl)-2-butyl-5H-pyrrolo[3,2-d]pyrimidin-7-yl)ethynyl)piperidine-1-carboxylate(83 mg, 0.160 mmol) in ethanol (20 mL) was passed through the H-cube(settings: 45° C., full hydrogen, 1 mL/min flow rate and 10% palladiumon carbon CatCart30 as the catalyst). The solution was passed throughthe H-cube again then the solution was evaporated in vacuo to yield awhite solid. The solid was dissolved in MeOH:DMSO (1:1) (1 mL) andpurified by MDAP (Method B) Appropriate fractions were combined andevaporated in-vacuo to yield a white solid (28 mg) A solution of thesolid (28 mg, 0.07 mmol) in anhydrous methanol (3 mL) and 4M hydrogenchloride in 1,4-dioxane (0.175 mL, 0.7 mmol) was stirred at roomtemperature for 74 hours. The reaction was evaporated to dryness under astream of nitrogen to yield a yellow oil. The oil was dissolved inMeOH:DMSO (1:1) (1 mL) and purified by MDAP (Method B). Appropriatefractions were combined and evaporated in-vacuo to yield the titlecompound a white solid (16 mg).

LCMS (System B): t_(RET)=0.75 min; MH⁺ 302

Biological Evaluation

Compounds of the invention were tested for in vitro biological activityin accordance with the following assay.

Assay for the Induction of Interferon-α and TNF-α Using Fresh HumanWhole Blood (WB) Compound Preparation

Compounds were prepared at 100× required concentration in DMSO inflat-bottom microtitre plates at a volume of 1.5 μL. Columns 1-10contained a 1 in 4 serial dilution of the test compound. Included oneach plate was a serial dilution of the TLR7/8 agonist resiquimod as astandard and Column 11 contained 1.5 μl of 200 μM resiquimod (giving a 2μM final concentration, used to define the approximate maximal responseto resiquimod). Each compound was assayed in duplicate for each donor.

Incubation and Assays for Interferon-α and TNF-α

Blood samples from three human donors were collected into sodium heparin(10 U/ml). 150 μl of whole Blood was dispensed into Col 1 to 11 of assayplates containing 1.5 μl of test compound or standard in DMSO. Plateswere placed in an incubator overnight (37° C., 95% air, 5% CO₂).Following the overnight incubation, plates were removed from theincubator & mixed on an orbital shaker for approximately 1 minute. 100μl of 0.9% saline was added to each well and the plates mixed again onan orbital shaker. Plates were then centrifuged (2500 rpm, 10 mins),after which a sample of plasma was removed using a Biomek FX and assayedfor both IFN-α and TNF-α using the MSD (Mesoscale Discovery)electrochemiluminescence assay platform. The IFN-α assay was carried outsimilarly to that described above. The TNF-α assay was carried out asper kit instructions (Cat No K111BHB).

Cytokine released was expressed as a percentage of the 2 μM resiquimodcontrol (column 11). This percentage was plotted against compoundconcentration and the pEC₅₀ for the response determined by non-linearleast squares curve fitting. For the IFN-α responses, generally a 4parameter logistic model was selected. For the TNF-α responses where aclear maximum response was obtained (i.e. a well defined plateau in theresponse was observed) then a 4 parameter model was generally used. Ifthe upper asymptote of the curve wasn't well defined then the curvefitting was generally constrained to a maximal response of 100% (i.e. tothe response to 2 μM resiquimod) or to the response of the highestconcentration tested if this was greater than the resiquimod response.Some curves were bell shaped for one or both cytokines and the cytokinedata on the down slope of the bell shaped response (i.e. concentrationsabove those giving the maximal response) were generally excluded fromthe fit, usually with the exception of the concentration immediatelyabove the peak response. Curve fitting thus concentrated on the up slopeof the dose response curve.

Results

Examples 1 to 3 had a mean pEC₅₀ for INF-α of ≧6.4.

Examples 1 to 3 had a mean pEC₅₀ for TNF-α of ≧5.0.

What is claimed is: 1.-24. (canceled)
 25. A compound of formula (I), ora salt thereof:

wherein: R₁ is n-C₃₋₆alkyl; R₂ is hydrogen or methyl; R₃ is hydrogen orC₁₋₆alkyl; m is an integer having a value of 0 to
 3. 26. The compound orsalt thereof according to claim 25 wherein R₁ is n-butyl.
 27. Thecompound or salt thereof according to claim 25 wherein R₂ is hydrogen.28. The compound or salt thereof according to claim 25 wherein m is aninteger having a value of 0 or
 1. 29. The compound or salt thereofaccording to claim 25 wherein R₃ is isopropyl.
 30. The compound or saltthereof according to claim 25 selected from the group consisting of:2-butyl-7-(3-(piperidin-4-yl)propyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;2-butyl-7-(3-(1-isopropylpiperidin-4-yl)propyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine;and2-butyl-7-(2-(piperidin-4-yl)ethyl)-5H-pyrrolo[3,2-d]pyrimidin-4-amine.31. The compound according to claim 25, which is in the form of apharmaceutically acceptable salt.
 32. The compound according to claim25, which is in the form of a free base.
 33. A pharmaceuticalcomposition comprising the compound as defined in claim 25, or apharmaceutically acceptable salt thereof, and one or morepharmaceutically acceptable excipients.
 34. A vaccine compositioncomprising the compound as defined in claim 25, or a pharmaceuticallyacceptable salt thereof, and an antigen or antigen composition.
 35. Amethod of treatment of allergic diseases and other inflammatoryconditions, infectious diseases and cancer, which method comprisesadministering to a human subject in need thereof, a therapeuticallyeffective amount of the compound as defined in claim 25, or apharmaceutically acceptable salt thereof.
 36. A method of treatment ofallergic rhinitis, which method comprises administering to a humansubject in need thereof, a therapeutically effective amount of thecompound as defined in claim 25, or a pharmaceutically acceptable saltthereof.
 37. A method of treatment of asthma, which method comprisesadministering to a human subject in need thereof a therapeuticallyeffective amount of the compound as defined in claim 25, or apharmaceutically acceptable salt thereof.
 38. A method of treating orpreventing disease comprising the administration to a human subjectsuffering from or susceptible to disease, a vaccine compositioncomprising the compound as defined in claim 25, or a pharmaceuticallyacceptable salt thereof, and an antigen or antigen composition.
 39. Amethod of treating or preventing disease comprising the administrationto a human subject suffering from or susceptible to disease, a vaccinecomposition as defined in claim 34.